Cell Stem Cell
Volume 29, Issue 2, 3 February 2022, Pages 265-280.e6
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Article
Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load

https://doi.org/10.1016/j.stem.2021.11.003Get rights and content
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Highlights

  • Yap/Taz in mesenchymal progenitor cells of loaded muscles induce MuSC proliferation

  • Expression of Thbs1 in mesenchymal progenitors during overload depends on Yap/Taz

  • The Thbs1-CD47 axis regulates MuSC proliferation in overloaded muscles

  • CD47 activation induces MuSC proliferation in calcitonin receptor mutant muscles

Summary

Adaptation to mechanical load, leading to enhanced force and power output, is a characteristic feature of skeletal muscle. Formation of new myonuclei required for efficient muscle hypertrophy relies on prior activation and proliferation of muscle stem cells (MuSCs). However, the mechanisms controlling MuSC expansion under conditions of increased load are not fully understood. Here we demonstrate that interstitial mesenchymal progenitors respond to mechanical load and stimulate MuSC proliferation in a surgical mouse model of increased muscle load. Mechanistically, transcriptional activation of Yes-associated protein 1 (Yap1)/transcriptional coactivator with PDZ-binding motif (Taz) in mesenchymal progenitors results in local production of thrombospondin-1 (Thbs1), which, in turn, drives MuSC proliferation through CD47 signaling. Under homeostatic conditions, however, CD47 signaling is insufficient to promote MuSC proliferation and instead depends on prior downregulation of the Calcitonin receptor. Our results suggest that relayed signaling between mesenchymal progenitors and MuSCs through a Yap1/Taz-Thbs1-CD47 pathway is critical to establish the supply of MuSCs during muscle hypertrophy.

Keywords

mechanical load
mesenchymal progenitors
muscle satellite cells
Yap
Taz
Thbs1
CD47
CalcR

Data and code availability

RNA-sequencing datasets generated during this study are available at Gene Expression

Omnibus (GEO), accession number GEO: GSE159082 and GEO: GSE162827.

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